Fibrinogen-beta gene haplotype is associated with mortality in sepsis Sanjay Manocha, James A. Russell, Ainsley M. Sutherland, Anan Wattanathum, Keith R. Walley* Critical Care Research Laboratories, James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, University of British Columbia, St. Paul’s Hospital, 1081 Burrard Street, Vancouver, BC, Canada V6Z 1Y6 Accepted 3 October 2006 Available online 20 November 2006 KEYWORDS Single nucleotide polymorphisms; Fibrinogen; Sepsis; Outcomes; Critical care Summary Objectives: Fibrinogen plays a key role in coagulation and inflammation. Tran- scription of the fibrinogen-beta gene (FGB) is the rate-limiting step in fibrinogen production. Our aim was to determine whether haplotypes of FGB are associated with mortality and organ dysfunction in a cohort of patients with sepsis. Methods: A prospective cohort of 631 consecutive Caucasian patients with sepsis from a ter- tiary care medicalesurgical ICU were enrolled in a gene association study. Patients were genotyped for three polymorphisms in FGB: À854 G/A, À455 G/A, and þ9006 G/A. Haplotypes were inferred using PHASE. The primary outcome was mortality. Secondary outcomes were severity of organ dysfunction as measured by days alive and free (DAF) of organ dysfunction. Results: Haplotype GAA was associated with a significantly lower 28-day mortality (28.9% vs. 36.9% for all other haplotypes, p Z 0.03). Carriers of two copies of haplotype GAA (vs. one and zero copies) had more DAF of organ dysfunction. In a multivariate analysis, haplotype GAA was an independent predictor for lower mortality (OR Z 0.66, 95% CI Z 0.46e0.94, p Z 0.02). Conclusions: Haplotype GAA in FGB is associated with lower mortality and lower severity of organ dysfunction. Haplotype GAA encompasses a previously described haplotype À1420A/ À854G/À455A/À249C/À148T/þ1690G that is associated with higher fibrinogen levels. ª 2006 The British Infection Society. Published by Elsevier Ltd. All rights reserved. Introduction The efficacy of many therapeutic interventions depends on severity of illness and risk of adverse outcomes. For example, the FDA has recommended that treatment with activated Protein C ‘‘is indicated for the reduction of mortality in adult patients with severe sepsis who have a high risk of death’’. 1 The risk of death from infection has a very high heritability component; greater than the herita- bility of dying of cancer or cardiovascular disease. 2 Thus, genotyping could be useful for the identification of patients at high risk of death in order to select appropriate thera- peutic interventions. * Corresponding author. Tel.: þ1 604 806 8136; fax: þ1 604 806 8351. E-mail address: kwalley@mrl.ubc.ca (K.R. Walley). 0163-4453/$30 ª 2006 The British Infection Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jinf.2006.10.001 www.elsevierhealth.com/journals/jinf Journal of Infection (2007) 54, 572e577